Abstract
We previously showed that hepatitis B virus (HBV) X protein (HBx) could promote the trimethylation of histone H3 lysine 9 (H3K9me3) to repress tumor suppressor genes in hepatocellular carcinoma (HCC). In this work, we analyze 23,148 human promoters using ChIP-chip to determine the effects of HBx on H3K9me3 enrichments in hepatoma cells with transfection of HBx-expressing plasmid. Immunohistochemistry for HBx and H3K9me3 was performed in 21 cases of HBV-associated HCC tissues. We identified that H3K9me3 immunoreactivity was significantly correlated with HBx staining in HCC tissues. ChIP-chip data indicated that HBx remarkably altered promoter enrichments of H3K9me3 in hepatoma cells. We identified 25 gene promoters, whose H3K9me3 enrichments are significantly altered in hepatoma cells transfected HBx-expressing plasmid, including 19 gaining H3K9m3, and six losing this mark. Most of these genes have not been previously reported in HCC, and BTBD17, MIR6089, ZNF205-AS1 and ZP1 have not previously been linked to cancer; only two genes (DAB2IP and ZNF185) have been reported in HCC. Genomic analyses suggested that genes with the differential H3K9me3 enrichments function in diverse cellular pathways and many are involved in cancer development and progression.
Highlights
Hepatitis B virus (HBV) chronic infection has been comfirmed as a major risk factor in the development of hepatocellular carcinoma (HCC) [1, 2]
We previously showed that hepatitis B virus (HBV) X protein (HBx) could promote the trimethylation of histone H3 lysine 9 (H3K9me3) to repress tumor suppressor genes in hepatocellular carcinoma (HCC)
We used a Chromatin immunoprecipitation (ChIP)-chip microarray, which enables the genome-wide identification of binding sites of transcription factors and chromatin regulators [12, 13], and examined the influence of Hepatitis B virus X protein (HBx) on H3K9me3 enrichment profiles on promoter regions to test the hypothesis that H3K9me3 was associated with the pathogenesis of HBV-associated HCC [10, 11]
Summary
Hepatitis B virus (HBV) chronic infection has been comfirmed as a major risk factor in the development of hepatocellular carcinoma (HCC) [1, 2]. Hepatitis B virus X protein (HBx), the product of the HBV gene HBX, is a pivotal factor in regulating gene transcription, participating in cell signaling, controlling cell proliferation, and immune response [2,3,4]. Several studies have indicated that HBx is involved in the tumorigenesis of HCC via histone modifications [4, 6]. Our previous studies demonstrated that HBx could promote both H3K9 trimethylation and DNA hypermethylation on the p16 promoter in hepatocarcinogenesis [10, 11]. These findings implicated that HBx-mediated H3K9me might be involved in the tumor suppressor gene silencing in carcinogenesis. The effects of HBx on H3K9me enrichment profiles on gene promoters were not fully understood
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